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A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis

Masschelein, Joleen, Sydor, Paulina K., Hobson, Christian, Howe, Rhiannon, Jones, Cerith ORCID:, Roberts, Douglas M., Yap, Zhong Ling, Parkhill, Julian, Mahenthiralingam, Eshwar ORCID: and Challis, Gregory L. 2019. A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis. Nature Chemistry 11 , pp. 906-912. 10.1038/s41557-019-0309-7

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Polyketide synthases assemble diverse natural products with numerous important applications. The thioester intermediates in polyketide assembly are covalently tethered to acyl carrier protein domains of the synthase. Several mechanisms for polyketide chain release are known, contributing to natural product structural diversification. Here, we report a dual transacylation mechanism for chain release from the enacyloxin polyketide synthase, which assembles an antibiotic with promising activity against Acinetobacter baumannii. A non-elongating ketosynthase domain transfers the polyketide chain from the final acyl carrier protein domain of the synthase to a separate carrier protein, and a non-ribosomal peptide synthetase condensation domain condenses it with (1S,3R,4S)-3,4-dihydroxycyclohexane carboxylic acid. Molecular dissection of this process reveals that non-elongating ketosynthase domain-mediated transacylation circumvents the inability of the condensation domain to recognize the acyl carrier protein domain. Several 3,4-dihydroxycyclohexane carboxylic acid analogues can be employed for chain release, suggesting a promising strategy for producing enacyloxin analogues.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Nature Publishing Group
ISSN: 1755-4330
Date of First Compliant Deposit: 16 September 2019
Date of Acceptance: 12 July 2019
Last Modified: 29 Nov 2023 13:15

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